Bioprocess vessels with integrated pump

ABSTRACT

A bioprocess vessel includes a flexible bag or substantially rigid container that defines an interior volume and having a bottom surface, the bottom surface being open or containing an aperture therein for the passage of fluid. A pump is secured to the bottom surface of the flexible bag or substantially rigid container. In some embodiments is secured directly to the flexible bag or substantially rigid container. In other embodiments, the pump is secured indirectly the flexible bag or substantially rigid container using, for example, a port that extends through the aperture on the bottom surface. The port or flanged surface may also be integrated into the pump, which is secured to the vessel. An optional mixing adaptor may be provided inside the interior volume of the flexible bag or substantially rigid container and at least partially covers the inlet that leads to the pump.

RELATED APPLICATION

This Application is a continuation of U.S. Application No. 17/720,241filed on Apr. 13, 2022, now allowed, which is a continuation of U.S.Application No. 16/480,070 filed on Jul. 23, 2019, now issued as U.S.Pat. No. 11,331,248, which is a U.S. National Stage filing under 35U.S.C. § 371 of International Application No. PCT/US2018/015777, filedJan. 29, 2018, which claims priority to U.S. Provisional Pat.Application No. 62/452,783 filed on Jan. 31, 2017, which is herebyincorporated by reference in its entirety. Priority is claimed pursuantto 35 U.S.C. § 119 and any other applicable statute.

TECHNICAL FIELD

The field of the invention generally relates to fluid-based systems andprocesses used in the manufacture, production, or capture of products.More specifically, the invention pertains to bioprocess fluidcontainers, media and buffer bags, reactors, and fermentation units usedin connection with pharmaceutical and biological applications or otherhygienic process industries.

BACKGROUND

Many commercial products are produced using chemical as well asbiological processes. Pharmaceuticals, for example, are produced incommercial quantities using scaled-up reactors and other equipment.So-called biologics are drugs or other compounds that are produced orisolated from living entities such as cells or tissue. Biologics can becomposed of proteins, nucleic acids, biomolecules, or complexcombinations of these substances. They may even include living entitiessuch as cells. For example, in order to produce biologics on acommercial scale, sophisticated and expensive equipment is needed. Inboth pharmaceutical and biologics, for example, various processes needto occur before the final product is obtained. In the case of biologics,mammalian cells may be grown in a container such as a growth chamber,reactor, bag or the like and nutrients may need to be carefullymodulated into the unit holding the cells.

Importantly, biologic products produced by living cells or otherorganisms may need to be filtered, extracted, concentrated, andultimately collected from the growth container. Waste products producedby cells typically have to be removed on a controlled basis from thegrowth container. Typically, desired biologic products produced by cellsand/or waste products are pumped out of the container where growthoccurs using a separate pumping device that is located downstream withrespect container containing the cells. This pumped fluid that isremoved from the growth chamber is typically subject to downstreamprocessing such as separation or filtration. Filtration is performed toseparate or concentrate a fluid solution and in biotechnology andpharmaceutical manufacturing processes is critical for the successfuland efficient production of drugs and other desirable products.

Various separation and filtration devices can be used to process thefluid pumped of the container unit where cell growths occurs. One commontechnique that is used to filter or separate components from the fluidis tangential flow filtration (TFF) where a filter or membrane is usedto filter species contained in the fluid based on, for example, physicalsize. The flow is tangential to the membrane to reduce the accumulationof waste products, dead cells, and biofilm that tends to clog the filtermembrane. Another separation technique utilizes acoustic wave separation(AWS) technology for cell harvesting and clarification. In contrast tomethods like TFF, AWS does not achieve separation of cells using aphysical barrier or filter, but with high-frequency resonant ultrasonicwaves.

More recently, perfusion methods for growing cells have been developed.In the perfusion method, culture medium which is depleted of nutrientsand contains waste products generated by the cells, is continuouslyremoved from the cell culture and replaced with fresh culture media. Theperfusion method enables one to achieve high concentrations of cells andpermits the production process to run continuously unlike batch process.In perfusion methods, there still is a need to separate and/or filterthe generated drugs and waste products from the continuously circulatecells. Perfusion methods, however, are known to have lower reliabilitybecause the cells are frequently damaged during the separation and/orfiltration process which separates the medium from the cells. Varioussolutions have been proposed to address the known disadvantages ofperfusion growth methods. U.S. Pat. No. 6,544,424 discloses a fluidfiltration system that attempts to address the low reliability ofperfusion methods. The system described in the ‘424 patent utilizes ahollow fiber module that is coupled at one end to a separate diaphragmpump. The pump is used to generate alternating flow across follow fibersor a filter screen.

A problem with solutions such as that disclosed in the ‘424 patent isthat the separate pump located downstream of the vessel containing cellsis connected to the vessel through various conduits and the hollow fibermodule. When incorporating pumps into fluid pathways, there is a need todesign such systems to avoid problems caused by cavitation, vacuum orpulsed flow condition. Cavitation and non-steady flow conditions tend tolyse the delicate mammalian cells that are used in these manufacturingprocesses. Pumping and vessel systems must therefore be designed toavoid these problems. Technically, this means that the pump and systemmust be designed such that the Net Positive Suction Head Available(NPSH_(A)) exceeds the Net Positive Suction Head Available Required(NPSH_(R)) to ensure the pump will operate without cavitation or otheradverse flow conditions. Unfortunately, when pumps are placed downstreamfrom the container like that disclosed in the ‘424 patent, thisinevitably tends to produce cavitation, vacuum, and problematic flowconditions that tend to kill or disrupt cells.

In addition, in many cell growth systems like those discussed above, aflexible segment of tubing connects the cell-containing vessel to thepump and any associated filtration/separation devices. Unfortunately,this configuration as illustrated in FIG. 1 suffers from a problem inthat due to upstream “negative” pumping pressure, the flexible tubingmay collapse in on itself as seen in the inset of FIG. 1 . This collapseof the tubing causes the inner surfaces of the tubing to contact oneanother and thereby prevents the further flow of fluid in the tubing.Even if the tubing does not fully close off, the presence of the tubingmay lead to cavitation and other deleterious pulsatile flow conditions.For example, the irregular and often tortious paths of the tubing orconduit disrupts the fragile state of cells. These flow conditions maycause damage to the pump as well as disrupting and interfering with thecells contained in the fluid.

SUMMARY

In one embodiment, a fluid vessel for containing biological fluidsincludes a pump that is either directly or indirectly incorporated intothe fluid vessel. In one embodiment, a hole or aperture is located in abottom surface of the vessel that allows passage of fluid out (or intothe vessel). The hole or aperture, in some embodiments, may actuallyencompass most or all of the bottom surface of the vessel, leaving aperimeter or circumferential surface to which the pump is adhered to.The pump is incorporated into the vessel at the location of the apertureor opening at the bottom of the vessel. In some embodiments, the pump issecured to the vessel through an intermediate component such as a portor flange that passes through the aperture and is secured to the vesselin a fluid tight arrangement (or manufactured in conjunction with thevessel). The pump is then secured to the flange. In another embodiment,the pump is directly secured to the vessel. For example, the pump headof the pump may be integrally formed with the vessel during themanufacturing process. Alternatively, in still another embodiment, thepump head may be secured to the vessel using one or more fasteners. Thepump head may also be directly bonded to the vessel using thermalbonding, an adhesive, glue, weld, or the like

In one embodiment, the fluid vessel is a substantially rigid container.For example, the vessel may take the form of a tub, vat, barrel, bottle,tank, flask, or other container suitable for holding liquids. The fluidvessel may be incorporated into processes, in some embodiments, wherethe vessel is used as a bioreactor or fermenter. The fluid vessel may bemade of any number of materials including metals, polymers, glass, andthe like. In one preferred embodiment, the vessel is formed from apolymer or resin material and is made as a single-use device. Likewise,one or more portions of the pump (e.g., pump head) that is directly orindirectly secured to the vessel may also be made from a polymer orresin material which facilitates integration or bonding of the pump tothe vessel. In some embodiments, both the pump and vessel are made fromsame material. In other embodiments, the pump and vessel are made fromdifferent materials.

In another embodiment, the fluid vessel is flexible container such as abag. The bag is typically made from polymer or resin material(s) and mayhave any number of shapes and sizes. The flexible bag may be formed frommultiple layers. The bag includes a pump that is directly or indirectlysecured to a bottom surface of the bag. The bag and attached orintegrated pump may be carried in a trolley, dolly, cradle, cart,holder, or other support container to hold the bag and pump in theproper orientation. In some embodiments, both the pump and bag are madefrom the same material. In other embodiments, the pump and bag are madefrom different materials.

In one embodiment, regardless of whether the vessel is flexible orsubstantially rigid, the pump includes a separate motor that is used topower and operate the pump. For example, one preferred embodiment of thepump is a diaphragm pump because of the gentle nature of the flowsproduced during operation. A diaphragm pump or membrane pump operates aspositive displacement pump that uses moving membrane in combination withvalves to pump fluid. In one embodiment, the drive shaft of the motormay be used to drive a nutating disk or wobble plate to actuate thediaphragm membrane to drive fluid through the pump. Alternatively, servomotors or electronic/magnetic actuators may be used to sequentiallyactuate the diaphragm membrane to achieve a similar pumping action. Thepump includes an inlet port that receives the incoming fluid that passesthrough the aperture in the vessel or the open vessel bottom and anoutlet port through which the pumped fluid passes.

In one embodiment of the invention the vessel itself is made to besingle use or disposable. In addition, one or more components of thepump may be made disposable. For example, the pump head which in someembodiments is integrally formed with the vessel may be disposable orcontain disposable components. In other embodiments where the pump headis secured to the vessel, the pump head may also be formed from one ormore components that are single use components. Alternatively, thevessel, pump, and any interface components between the two like a portor flange may be sterilizable for reuse. The motor or other drivemechanism that is used to power and operate the pump is typicallyreusable.

In one embodiment, a bioprocess vessel having an integrated pump is aflexible bag that incorporates a pump. The flexible bag defines aninterior volume and having a bottom surface, the bottom surfacecontaining an aperture therein for the passage of fluid. The bioprocessvessel includes a pump having an inlet and an outlet, the pump beingsecured to the bottom surface of the flexible bag whereby fluid passesfrom the interior volume of the flexible bag and into the inlet of thepump.

In another embodiment, a single-use bioprocess vessel having anintegrated pump is disclosed. The single-use bioprocess vessel includesa substantially rigid container formed from a resin or polymer materialdefining an interior volume and having a bottom surface. The single-usebioprocess vessel includes a pump having an inlet and an outlet, thepump being secured to the bottom surface of the substantially rigidcontainer whereby fluid passes from the interior volume of thesubstantially rigid container and into the inlet of the pump. Thesingle-use bioprocess vessel may take the form of a bioreactor or afermentation unit.

The vessels described herein may include an optional mixing adapter thatis secured either to the vessel itself or to the pump. The mixingadapter at least partially covers a portion of the inlet to the pump.The mixing adapter may be used to prevent solids and other materialsthat are fed into the vessel from directly entering the inlet of theport prior to properly mixing with the fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a configuration of a bag and pump according to theprior art.

FIG. 2A illustrates an exploded view of a vessel in the form of aflexible bag that contains an integrated pump according to oneembodiment.

FIG. 2B illustrates a side view of the flexible bag with integrated pumpof FIG. 2A.

FIG. 2C illustrates a cross-sectional view of the flexible bag withintegrated pump of FIG. 2A.

FIG. 2D illustrates a perspective view of a flexible bag illustratingthe aperture formed in the bottom surface (no port is illustrated).

FIG. 2E illustrates a perspective view of a flexible bag illustratingthe port disposed in the bottom surface of the flexible bag.

FIG. 2F illustrates a perspective view of a port that is disposed in theaperture of the flexible bag according to one embodiment. The portincludes a flanged surface that is, in one embodiment, welded, bonded,or otherwise adhered to the flexible bag. The opposing end of the porthas a connector end that is used to connect the pump.

FIG. 2G illustrates one embodiment of a pump head.

FIG. 3A illustrates an exploded view of a vessel in the form of aflexible bag that contains an integrated pump according to anotherembodiment.

FIG. 3B illustrates a cross-sectional view of the flexible bag withintegrated pump of FIG. 3A.

FIG. 3C illustrates a perspective view of the mixing adapter accordingto one embodiment.

FIG. 4A illustrates an exploded view of a vessel in the form of aflexible bag that contains an integrated pump according to anotherembodiment.

FIG. 4B illustrates a perspective view of the mixing adapter accordingto another embodiment.

FIG. 4C illustrates another perspective view (showing underside) of themixing adapter of FIG. 4B.

FIG. 5A illustrates an exploded view of a vessel in the form of aflexible bag that contains an integrated pump according to anotherembodiment.

FIG. 5B illustrates a cross-sectional view of the flexible bag withintegrated pump of FIG. 5A.

FIG. 6A illustrates an exploded view of a vessel in the form of aflexible bag that contains an integrated pump according to anotherembodiment.

FIG. 6B illustrates a cross-sectional view of the flexible bag withintegrated pump of FIG. 6A.

FIG. 6C illustrates a perspective view of a pump head used with theembodiment of FIG. 6B.

FIG. 7A illustrates an exploded view of a vessel in the form of a tank(e.g., bioreactor or fermenter) that contains an integrated pumpaccording to another embodiment.

FIG. 7B illustrates a side view of the embodiment of FIG. 7A.

FIG. 8A illustrates an exploded view of a vessel in the form of a tank(e.g., bioreactor or fermenter) that contains an integrated pumpaccording to another embodiment.

FIG. 8B illustrates a side view of the embodiment of FIG. 8A.

FIG. 9 illustrates one embodiment of the vessel used as a perfusionbioreactor and mounted on a table or support.

FIG. 10 illustrates one embodiment of a carrier in the form of a dollyor trolley that is used to hold a flexible bag with the integrated pump.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

FIGS. 2A-2G illustrates one embodiment of a vessel 10 in the form of aflexible bag 12 that contains an integrated pump 14. The flexible bag 12defines an interior volume that is used to hold fluids therein. Theinterior of the flexible bag 12 defines a sterile or aseptic environmentin which fluid reagents or products are contained. The flexible bag 12includes a number of side surfaces 16 as well as a top surface 18 and abottom surface 20. The flexible bag 12 may have any number of shapes andsizes (e.g., one hundred liters or less to thousands of liters). Theflexible bag 12 is illustrated in FIGS. 2A-2E has discrete surfaces(e.g., top, sides, bottom) although in some embodiments there need notbe such discrete demarcations. The flexible bag 12 includes top surface18 that, in some embodiments, may include one or more ports 22 thatdefine access passageways to the interior of the flexible bag 12. Theports 22 may provide access for the addition of materials includingsolids, liquids, and gases. The port(s) 22 may also be used to samplefluid contained in the flexible bag 12. The ports 22 may also provideaccess for one or more probes or sensors that are used to monitorconditions within the interior of the flexible bag 12. The port 22 mayalso provide access for a mixer or agitation device. The ports 22 haveany number of different sizes and configurations. While the ports 22 areillustrated being located in the top surface 18 the ports 22 may belocated on any surface of the flexible bag 12. For example, a port 22may be located at a side of the flexible bag 12 near the bottom surface20 to provide access for a mixer device or the like.

The flexible bag 12 further includes a bottom or lower surface 20. Thebottom surface 20 refers to the lowermost surface of the flexible bag 12when oriented in the operational state. As explained herein, the fluidcontained in the flexible bag 12 is pumped out of the flexible bag 12 atthe bottom surface 20. This ensures that the fluid contained in theflexible bag always primes the pump 14. In addition, this ensures thatall the fluid contained in the flexible bag 12 can be evacuated from theflexible bag 12 using the pump 14 (i.e., minimize or eliminate any deadvolume in the system).

The flexible bag 12, in one embodiment, is made from one or morepolymers or resin materials. For example, medical-grade resins compliantwith class VI standards may be used. Additional examples includepolyethylene (e.g., low density polyethylene (LDPE) or ultra-low densitypolyethylene (ULDPE) or polypropylene (PP), ethylene vinyl acetate(EFA), polyethylene terephthalate (PET), polyvinyl acetate (PVA),polyvinyl chloride (PVC), and the like are also contemplated. In someembodiments, the flexible bag 12 may by formed from multiple layers. Forexample, the inner layer that contacts the fluid may be made from LDPE.A second layer of polyvinyl acetate (PVA) or flexible polyvinyl chloride(PVC) may be used as an intermediate layer. An outer layer of LDPE orPET may provide mechanical strength. It should be appreciated that theintegrated pump 14 embodiments described herein may be used with anynumber of different construction types, materials, and layers used forthe flexible bag 12.

The pump 14 may be connected to the flexible bag 12 directly orindirectly as explained herein. A direct connection connects one or moresurfaces of an inlet of the pump 14 to the flexible bag 12. In contrast,an indirect connection connects the pump 14 to the flexible bag 12 usinga port 24. The embodiment illustrated in FIGS. 2A-2G utilizes a port 24.In either embodiment, there is no flexible conduit or tubing that isconnected to the inlet of the pump 14 from the flexible bag 12. Instead,the inlet of the pump 14 is connected to the flexible bag 12 via theport 24 to interior of the flexible bag 12. In this regard, there is noconcern with flexible tubing that collapses upon itself as illustratedin FIG. 1 .

With reference to FIG. 2D, the flexible bag 12 includes an aperture 26formed in the bottom surface 20 that permits the passage of fluidcontained therein and serves as the inlet to the pump 14. Note that inthis illustration the port 24 is removed to illustrate the aperture 26.The aperture 26 is typically circular in shape although other shapes arecontemplated. The aperture 26 dimensions may vary depending upon thesize of the flexible bag 12. FIG. 2E illustrates the flexible bag 12with the port 24 disposed in the aperture.

In the embodiment illustrated in FIGS. 2A-2G, a port 24 is disposedinside the aperture 26 and is used as a connector to the pump 14 andalso permits the passage of fluid contained in the flexible bag 12. FIG.2F illustrates an isolated perspective view of the port 24. The port 24includes a central aperture 25 that permits the passage of fluid throughthe port 24 and into the pump 14. The port 24 may be made from anynumber of materials including polymers materials such, for example, aspolypropylene and polycarbonate, LDPE, high-density polyethylene (HDPE),or other medical-grade plastics or resins. The port 24 may even beformed from metal in some embodiments. In some embodiments, the port 24is formed from the same material used for the flexible bag 12. In otherembodiments, the port 24 is formed from a material that is differentfrom the flexible bag 12. In the embodiment of FIGS. 2A-2G, the port 24includes a first flanged surface 28 that is secured to the bottomsurface 20 of the flexible bag 12. The first flanged surface 28 issecured to the bottom surface 20 of the flexible bag 12 in a fluid-tightseal. The first flanged surface 28 may be secured to an internal surfaceof the bottom surface 20 or an external surface of the bottom surface20. Any number of ways of forming a fluid-tight seal with the bottomsurface 20 may be used. For example, the first flanged surface 28 may bewelded to the bottom surface 20 of the flexible bag 12. Any known methodof welding such components together including heat welding, resistivewelding, spin welding, friction welding, laser welding, and the like. Anadhesive may also be used to secure the first flanged surface 28 to thebottom surface 20. Alternatively, the port 24 may be integrally formedwith the flexible bag 12 during the manufacturing process (e.g., in themolding or formation of the flexible bag 12). The port 24 may also bemade from a polymer or resin material than can bond the flexible bag 12in response to, for example, applied heat.

The port 24 includes a second flanged surface 30 that is located on anopposing end of the port 24 and serves as a connector end to the port24. The second flanged surface 30 is disposed outside the flexible bag12 and is used as a connector to connect the pump 14. In one embodiment,the second flanged surface 30 is a tri-clamp (TC) type flanged surface30 that is commonly used in bioprocess and pharmaceutical systems. Intri-clamp connections two mating flanged surfaces are connected to oneanother at an interface that typically contains a ferrule gasket 33(seen in FIG. 2A) and a separate clamp 32 is used to secure the twocomponents together. In the embodiment of FIGS. 2A-2G, the pump 14includes corresponding connector end 34 that is secured to the secondflanged surface 30 using the clamp 32. While the TC flanged surface 30is illustrated it should be appreciated that other hygienic connectorssuch as male/female connectors, flange connectors, and the like(including proprietary connectors) may be used. Preferably, the port 24does not extend far out of the flexible bag 12 (i.e., it should be asshort as possible; yet still accommodate a clamp 32). Because theconnector end 30 interfaces with a pump 14, these connections maytypically be large, e.g., 6″, 8″, 10″, or 12″ diameter opening dependingon the size of the pump 14; although other sizes are contemplated.

With reference to FIGS. 2A-2C and 2G, the pump 14 includes a pump head40 and pump casing 41 that collectively contain the operating componentsof the pump 14. The pump head 40 includes an inlet 42 (FIGS. 2A and 2G)that is coupled to the flexible bag 12 by the connector end 34.Advantageously, the inlet 42 to the pump is directly connected to theflexible bag 12 via the connector end 34; there are no intervening tubesor conduits located between the pump 4 and the flexible bag 12. Theoutlet 43 of the pump 14 may terminate in a variety of ends orconnectors used in biopharmaceutical processes. These include hygienicconnectors, barb locks, hose barbs, flanges, TC connectors, disposableaseptic connectors (DAC), and the like. The outlet 43 may include orincorporate a valve directly or indirectly in the outlet 43. Tubing orother conduit may also interface directly with the outlet 43 of the pump14 (e.g., by welding to the outlet 43 or the like). In still anotherembodiment, the outlet 43 of the pump 14 may simply be an aperture oropening through which fluid passes. This aperture or opening may bethreaded internally so that the outlet 34 can accommodate a threadedconnecting component or insert that interfaces with the threaded outlet34 of the pump 14. This may include a connector (not shown) that isscrewed into the internally threaded outlet 43. The threaded connectingcomponent or insert may include any number of ends or connectors used inbiopharmaceutical processes such as those described herein.

The outlet 43 is generally illustrated being oriented generallyorthogonal to vertical axis of the flexible bag 12 (or substantiallyrigid container as explained below). It should be appreciated that theoutlet 43 may exit the pump 14 at an angle. For example, the outlet 43may be angled downward to facilitate easier usage. An angle (relative tohorizontal) of about 15° to 45° would be common, although other anglesare contemplated.

The pump 14, in one embodiment, operates as a diaphragm pump. Adiaphragm pump operates by the actuation of multiple diaphragms 44(FIGS. 2A and 2C) which are sequentially actuated to create a gentlepumping action of fluid through the pump. The diaphragms 44 work inconjunction with check-valves 46 to ensure the flow of fluid through thepump 14 in one direction. In one embodiment, actuation of the diaphragms44 is effectuated by a nutating or wobble plate 48 (FIGS. 2B and 2C)that rotates about an axis to sequentially activate the diaphragms 44.As seen in FIGS. 2A-2C, a motor 50 is secured to the pump 14 and iscoupled via a drive shaft (not shown) to the nutating disk or wobbleplate 48 to actuate the multiple diaphragms 44 and pump fluid throughthe pump 14 from the inlet 42 to the outlet 43. Any number of types ofmotors 50 may be used including direct current motors, alternatingcurrent motors, and the like.

While there are four (4) diaphragms 44 illustrated in FIG. 2A, it shouldbe understood that other configurations of the pump head 40 may containfewer or more diaphragms 44. For example, additional diaphragms 44 maymake for an even more smooth pumping action with reduced pulsatile floweffects. Likewise, while a motor 50 is illustrated as driving a nutatingdisk or wobble plate 48, an alternative construction of the pump 14 mayutilize individual actuators (e.g., servo, electric, magnetic, orpneumatic) to sequentially actuate the diaphragms 44 to achieve the samepumping action without the need for a rotating disk or wobble plate 48.Thus, the motor 50 may be replaced with one or more servo actuators,electric/magnetic actuators or the like.

The flexible bag 12 may be housed in an outer support container 150 orthe like such as that illustrated in FIG. 10 that holds the bags in theproper orientation during process operations (e.g., bottom surface 20 isheld closest to ground so that surface of fluid moves from top to bottomas it is being pumped out of the flexible bag 12). These may be locatedon a cart, dolly, trolley, or the like so that fluids can be quicklyconnected/disconnected to process operations as needed. As seen in FIG.2A, the flexible bag 12 may, in some embodiments, contain one or moreoptional hanging points 52 where the flexible bag 12 can be suspendedfrom. Because of the weight of the pump 14 and the motor 50, the motor50 may be secured to a support surface 160 or the like as is disclosedin FIG. 10 so as not put undue force on the flexible bag 12.

FIGS. 2A-2C illustrate an optional mixing adapter 60 that is used to atleast partially cover the aperture 26 in the flexible bag 12 accordingto one embodiment. The mixing adapter 60 is used to ensure thatmaterials such as powders or other solid media that may be added to theflexible bag 12 via a port 22 do not fall directly into the aperture 26where the materials could interfere with the operation of the pump 14.The mixing adapter 60 also aids in mixing the fluid. In particular, asseen in FIG. 2C, the mixing adapter 60 includes a top curved surface inone embodiment that at least partially covers the cross-sectional areaof the aperture 26 in the flexible bag 12. Fluid is able to enter theinlet 42 of the pump 14 around the sides of the mixing adapter. As seenin FIGS. 2B and 2C, the mixing adapter 60 may be secured to the pumphead and projects centrally within the inlet 42 of the pump 14. Themixing adapter 60 may be made from any compatible materials includingpolymers and resins such as those described herein as well as metal(e.g., stainless steel).

FIGS. 3A-3C illustrate another embodiment of a vessel 10 in the form ofa flexible bag 12 that contains an integrated pump 14. Similar elementsto those of the embodiment of FIGS. 2A-2G will retain the same referencenumbers for clarity. Unlike the embodiment of FIGS. 2A-2G, however,there is no separate port 28 that is placed in the aperture 26 of theflexible bag 12. In this embodiment, the pump head 40 of the pump 14 issecured to the flexible bag 12 using a plurality of fasteners 70 as seenin FIG. 3A that pass through corresponding holes or apertures in thebottom surface 20 of the flexible bag 12 and engage with mixing adapter72. With reference to FIG. 3C, the mixing adapter 72 in the illustratedembodiment includes domed or curved top surface along with a pluralityof standoffs 73 (e.g., legs, posts, boss) that contains apertures 74therein for receiving the fasteners 70. The fasteners 70 may includescrews (or bolts) that interface with corresponding holes or apertures74 formed in the mixing adapter 72.

In this embodiment, the mixing adapter 72 also acts as a connectionpoint for the pump 14. In this regard, the bottom surface 20 of theflexible bag 12 is interposed or pinched between the pump head 40 andthe mixing adapter 72. The mixing adapter 72 may include one or moreholes 75 in the surface thereof that allow the passage of fluid to theinlet 42 of the pump 14. Fluid also enters the inlet 42 of the pump 14by entering along the gap formed between the bottom surface 20 of theflexible bag 12 and the mixing adapter 72. As seen in FIG. 3A, acircumferential gasket 76 is interposed between the pump head 40 and thebottom surface 20 of the flexible bag 12. On the interior of theflexible bag 12, individual gaskets 77 are interposed between thestandoffs 73 of the mixing adapter 72 and the interior surface bottomsurface 20 of the flexible bag 12 to provide a fluid-tight seal.

FIGS. 4A-4C illustrate another embodiment of a vessel 10 in the form ofa flexible bag 12 that contains an integrated pump 14 that is modifiedfrom the embodiment of FIGS. 3A-3C. Again, similar elements to those ofthe embodiment of FIGS. 3A-3C will retain the same reference numbers forclarity. In this alternative embodiment, as best seen in FIGS. 4B and4C, the mixing adapter 72 includes a lower circumferential flange 78that is secured to the standoffs 73. The circumferential flange 78 mateswith a corresponding circumferential gasket 76 that is interposedbetween the bottom surface 20 of the flexible bag 12 and thecircumferential flange 78 when the fasteners 70 are used to secure thepump head 40 to the mixing adapter 72. In this embodiment, the separategaskets 77 are omitted.

FIGS. 5A and 5B illustrate another embodiment of a vessel 10 in the formof a flexible bag 12 that contains an integrated pump 14. Similarelements to those of prior embodiments are illustrated with the samereference numbers for clarity. In this embodiment, the pump 14 isdirectly bonded to or integrally formed with the flexible bag 12. Morespecifically, the pump head 40 is directly bonded to the bottom surface20 of the flexible bag 12. In this embodiment, the pump head 40 issecured to the flexible bag 12 by friction welding, ultrasonic welding,spin welding, laser welding, the use of an adhesive or glue, or otherknown bonding methods. The pump head 40 may also be integrally formedwith the flexible bag 12 during the manufacturing of the pump head 40and/or the flexible bag 12. In one embodiment, the pump head 40 mayinclude a contact surface that contacts the flexible bag 12 that isformed from the same material used in the flexible bag 12.Alternatively, the pump head 40 may include a contact surface thatcontacts the flexible bag 12 that is a different material yet stillprovides a secure, fluid-tight bond. FIGS. 5A and 5B illustrate anoptional mixing adapter 60 being used. It should be understood, however,that the pump 14 may still operate without the mixing adapter 60.

FIGS. 6A-6C illustrate another embodiment of a vessel 10 in the form ofa flexible bag 12 that contains an integrated pump 14. Similar elementsto those of prior embodiments are illustrated with the same referencenumbers for clarity. In this embodiment, the pump 14 includes a flangedend 79 that is bonded, welded, or otherwise secured to the bottomsurface 20 of the flexible bag 12. Specifically, the pump head 40includes a flanged end 79 that extends radially outward and is bonded,welded, or otherwise secured to the inner or liquid-facing surface ofthe bottom surface 20 of the flexible bag 12. FIG. 6A illustrates anexploded view of the vessel 10 and components according to thisembodiment. The pump head 40 includes a flanged end 79 at one endthereof that is bonded, welded, or otherwise secured to the flexible bag12 as seen in FIG. 6B. As seen in FIG. 6A, the aperture 26 in theflexible bag 12 is larger to accommodate the pump head 40. FIG. 6Cillustrates the pump head 40 having the flanged end 79 as well as theinlet 42 and outlet 43. While FIGS. 6A and 6B illustrate the flanged end79 being bonded, welded, or otherwise secured to the inner (or liquidfacing) of the bottom surface 20 of the flexible bag 12 it should beappreciated that the flanged end 79 may also be bonded, welded, orotherwise secured to the outer surface of the bottom surface 20 of theflexible bag 12.

FIGS. 7A and 7B illustrate yet another embodiment of a vessel 10 in theform of a substantial rigid container 80 that includes a pump 14 (bestseen in FIG. 7B) that is directly or indirectly secured to thesubstantially rigid container 80. The substantially rigid container 80may include a tub, vat, barrel, bottle, tank, flask, or the like. Thesubstantially rigid container 80 may be made, in one embodiment, in theform of a bioreactor or fermenter. The tank 82 includes one or more sidesurfaces and a bottom surface where the pump 14 is located. The tank 82may be circular as illustrated and may have a wide variety of volumes.It should be understood that the tank 82 may have any number ofgeometric shapes and sizes. Typically, the height of the tank 82 is atleast 1.5 times the diameter of the tank 82 but other sizes arecontemplated. In one embodiment, the substantial rigid container 80includes a liquid-containing tank 82 and a lid 84 that contains optionalports 86. These ports 86 may provide access to add or remove fluidcontaining the tank 82. The ports 86 may also hold or contain sensors orprobes that are used to monitor the conditions inside the tank 82. Theports 86 may also provide access to mixers, gas introducers, agitators,gas bubblers, and the like. The ports 86, in some embodiments, mayterminate in a variety of ends or connectors used in biopharmaceuticalprocesses. These include hygienic connectors, hose barbs, flanges, TCconnectors, disposable aseptic connectors (DAC), and the like. While theports 86 are illustrated in the lid 84 they may also be incorporatedinto the tank 82 itself (e.g., on the sidewalls) in some alternativeembodiments. For example, a port 86 may be located at a side of the tank82 near the bottom to provide access for a mixer device or the like.

The tank 82 and lid 84 may be made from a polymer, plastic material, orresin that mimics the performance of glass or stainless steel. Thepolymer material preferably complies with Class IV standards or higherlevels of biocompatibility and chemical resistance as needed, and isfree of or contains low amounts of leachable and extractable material.Examples of polymers that can be used to form the substantially rigidcontainer 80 include polyethylene, polycarbonate, and as well as thematerials noted above with respect to the flexible bag 12 embodiment.Medical-grade resins compliant with class VI standards may also be used.Alternatively, the tank 82 and/or lid 84 may be made from a metal suchas stainless steel. The tank 82 and/or lid 84 may also be made of glass.In some embodiments, the vessel 10 is designed as a single-use vessel 10that is discarded after a batch or continuous run of products hascompleted. In other embodiments, the vessel 10 may be designed to besterilized and reused.

In some embodiments, as best seen in FIG. 7A, the liquid-containing tank82 includes a shaft 88 that extends longitudinally along the length ofthe tank 82 and has mounted thereon an impeller 90. The rotating shaft88 and impeller 90 are used to mix fluid contained in the tank 82. Theshaft 88 may be coupled to a motor 91 to rotate the shaft 88 andimpeller 90 at the desired rotational speeds. FIGS. 8A and 8Billustrates an alternative embodiment of the substantial rigid container80 (e.g., tank 82 and lid 84) that employs an angled mixer that isformed by an angled shaft 88 that includes an impeller 90 mountedthereon. The angled shaft 88 passes through lid 84 where it interfaceswith the motor 91.

As seen in FIGS. 7B and 8B, a pump 14 is secured to the bottom surfaceof the tank 82. The bottom surface may a flat bottom surface of the tank82 or it may include a rim (e.g., circumferential rim) defined by thewall(s) of the tank 82. For example, as explained herein, the pump head92 may form at least part of the bottom surface of the tank 82. In oneembodiment, as seen in FIGS. 7A and 8A, the pump 14 includes a pump head92 or a portion of the pump head 92 that is integrated into the tank 82.For example, the tank pump 92 or portion thereof may be integrallyformed with the tank 82. This may occur during the molding operation inwhich the pump head 92 is integrally manufactured along with the tank 82(e.g., a unibody construction). Alternatively, the pump head 92 may besecured to the tank 82 by friction welding, ultrasonic welding, spinwelding, laser welding, the use of an adhesive or glue, or other knownbonding methods. For example, the pump head 92 or a portion thereon(e.g., upper portion 94 described below). In yet another alternative,the pump head 92 may be secured to the tank 82 using one or morefasteners similar to the embodiment of FIGS. 3A-3C or 4A-4C. In yetanother alternative, the pump head 92 may be secured to the tank 82using a port such as port 24 of FIG. 2F.

As seen in FIGS. 7A and 8A, the pump head 92 includes an upper headportion 94 that contains the fluid outlet 96 which is integrally formedwith the tank 82. The pump head 92 includes a lower portion 98 thatcontains the pumping mechanism, which in the illustrated embodiment is adiaphragm pump as previously explained, although other pump types may beused. For example, the pump head 92 may operate as a centrifugal pump.In some embodiments, the pump head 92 may be formed as a single orunitary piece instead of the two-piece construction as illustrated.Likewise, in still other embodiments, the pump head 92 may have morethan the upper and lower portions 94, 98.

The integral formation with the tank 82 may occur during themanufacturing process or the pump head 92 (e.g., one or more of upperportion 94 or lower portion 98) may be bonded together using one or moreof the bonding techniques described herein (e.g., thermal bonding, anadhesive, glue, weld, or the like). Thus, in some embodiments, the pumphead 92 or portions thereof such as the upper portion 94 and/or lowerportion 98 may be made from the same polymer or resin material that isused to form the tank 82. In other embodiments, the pump head 92 orportions thereof may be formed from different materials that are stillcompatible with bonding to the tank 82. The portion of the pump head 92that is bonded, welded, adhered, or integrated with the tank 82 (e.g.,the upper head portion 94) should, in one embodiment, preferably madefrom plastic or resin materials that are also compatible with thebioprocess or chemical process taking place inside the vessel 10. Theupper portion 94 of the pump head 92 includes a pump inlet 95 that isopen to and communicates with the interior of the tank 82. The bottom ofthe tank 82 may include an opening like aperture 26 in the flexible bag12 embodiment or the bottom of the tank 82 may be completely open andsealed off when the pump head 92 is secured thereto. Advantageously,there are no intermediate conduits or lines between the pump inlet 95and the tank 82 as the pump 14 is connected to the substantial rigidcontainer 80.

As seen in FIGS. 7A and 8A, the pump head 92 includes a lower headportion 98 that contains the pumping mechanism or drive components. Inone preferred embodiment, the lower head portion 98 contains thediaphragm pump components as described previously. This includes themultiple diaphragms 44 and check-valves 46 which are sequentiallyactuated as previously explained herein to create a gentle pumpingaction of fluid through the pump 14. In the embodiment of FIGS. 7A, 7B,8A, 8B, a motor 102 is secured to the lower head portion 98 using aplurality of fasteners or the like. The motor 102 is used tosequentially actuate the diaphragms 44 to pump fluid from the tank 82 tothe outlet 96. In one embodiment, actuation of the diaphragms 44 iseffectuated by a nutating or wobble plate 104 (FIGS. 7A, 7B, 8A and 8B)that rotates about an axis to sequentially activate the diaphragms 44.While a motor 102 is illustrated as driving a nutating disk or wobbleplate 104, an alternative construction of the pump 14 may utilizeindividual actuators (e.g., servo or pneumatic) to sequentially actuatethe diaphragms 44 to achieve the same pumping action without the needfor a rotating disk or wobble plate 104.

The outlet 96 of the pump 14 may terminate in a variety of ends orconnectors used in biopharmaceutical processes. These include hygienicconnectors, hose barbs, flanges, TC connectors, disposable asepticconnectors (DAC), and the like. In this embodiment, the motor 102 mayinclude a mounting plate 104 that can be mounted on a sturdy surface sothat the tank 82 may be held in a substantially upright orientation. Thesubstantial rigid container 80 of the embodiment illustrated in FIGS.7A, 7B, 8A, and 8B may contain an optional mixing adapter 60 like thatillustrated in FIGS. 2A, 2B, 2C, 5A or mixing adapter 72 illustrated inFIGS. 3A, 3B, 3C, 4A, 4B, 4C that is used to at least partially coverthe inlet 95 of the pump 14.

The outlet 96 may include or incorporate a valve directly or indirectlyin the outlet 96. Tubing or other conduit may also interface directlywith the outlet 96 of the pump 14 (e.g., by welding to the outlet 96 orthe like). In still another embodiment, the outlet 96 of the pump 14 maysimply be an aperture or opening through which fluid passes. Thisaperture or opening may be threaded internally so that the outlet 96 canaccommodate a threaded connecting component or insert that interfaceswith the threaded outlet 96 of the pump 14. This may include a connector(not shown) that is screwed into the internally threaded outlet 96. Thethreaded connecting component or insert may include any number of endsor connectors used in biopharmaceutical processes such as thosedescribed herein.

FIG. 9 illustrates one embodiment of the vessel 10 in the form of asubstantial rigid container 80 of FIGS. 7A, 7B, 8A, 8B being used as abioreactor. A table or other support 110 is provided for holding thevarious components in place. In this embodiment, the pump 14 isillustrated on the bottom of the tank 82 and the tank 82 is held in avertical orientation by the motor 102 that is mounted vertically to thetable or support 110 using support 112. The motor 102 and/or pump 14passes through an aperture 113 formed in the table or support 110. Asseen in FIG. 9 , one of the ports 86 in the cover 84 is connected to aconduit 114 that leads to a peristaltic pump 116. The peristaltic pump116 is coupled via another conduit 118 that leads to a tank 120 that, inone embodiment, holds fresh medium that is to be delivered to the tank82. In this regard, the peristaltic pump 116 is used to pump fresh fluidmedium into the tank 82. The outlet 96 of the pump head 92 is connectedto a diaphragm valve 122 via clamps 124. The outlet of the diaphragmvalve 122 is connected to a conduit 126 that leads to a filtration orseparation unit 128. In the embodiment illustrated n FIG. 9 , this is ahollow fiber filter module 128. For example, this may be a hollow fibertangential flow filter cartridge which are commercially available. Thefiltration or separation unit 128 may be any type of filter orseparation unit. These include conventional tangential flow filtrationunits, acoustic separators, and the like. The filtration or separationunit 128 is used to filter out desired end products (e.g., drugs) orwaste products via outlet port 130 while the non-filtered cells can bereturned back to the tank 82 via conduit 132. It should be appreciatedthat the particular arrangement illustrated in FIG. 9 is illustrativeand the vessels 10 described herein (including the flexible bag 12 andthe rigid container 80) may be used in any number of configurationsdepending on the application in which they are used.

The conduits 114, 118, 126, 132 of FIG. 9 may be made of any number ofbiocompatible materials including metals or polymers as silicone whichmay be either reinforced or un-reinforced. In one particular embodiment,the conduits 114, 118, 126, 132 are formed from an un-reinforced polymersuch as silicone and surrounding by sections or segments ofinterconnected rigid, external jackets such as those disclosed inInternational Pat. Publication No. WO 2016/100396 A1; also U.S. PatentApplication No. 15/535,601, which are incorporated by reference herein.

FIG. 10 illustrates one embodiment of a carrier 150 in the form of adolly or trolley that is used to hold a flexible bag 12 with theintegrated pump 14. The carrier 150 may be mobile or fixed. FIG. 10illustrates a mobile carrier 150 that uses a plurality of wheels 152 sothat the carrier 150 may be moved. The flexible bag 12 is containedwithin a bin 154 supported by a frame 155 that is dimensioned to hold oraccommodate the size of the flexible bag 12. The carrier 150 is formedfrom a sturdy material such as metal or plastic so that it canaccommodate the weight of the fluid contained in the flexible bag 12 andthe integrated pump 14. As seen in FIG. 10 , the bin 154 includes anaperture formed in the bottom surface so that the pump 14 and attachedmotor 158 are located external to and beneath the bin 154. The motor 158may mounted to a support 160 that is integrated in the frame 155 of thecarrier 150. The support 160 ensures that the pump 14 and motor 158 aregenerally oriented in the vertical direction and so that the weight ofthe pump 14 and motor 158 do not pull on the flexible bag 12.

FIG. 10 illustrates the pump outlet 43 connected to a diaphragmreplacement valve 162 that is connected to a conduit 164. For example,this may include a diaphragm replacement valve (DRV) sold by AquasynLLC, Carson City, NV. The ports 22 on the flexible bag 12 are alsoillustrated, in this particular depiction, being connected to a variousconduits, tubing, or connectors 166, 168. These may be connected to theports 22 using, for example, clamps 170. The types of conduits 164,tubing, and connectors 166, 168 may vary depending on the particularapplication in which the flexible bag 12 is used. The conduits 164,tubing, and connectors 166, 168 may be formed from a rigid material suchas a metal (e.g., stainless steel) or they may be formed from a polymermaterial. For example, the conduit 164 or tubing may be formed fromsilicone or the like for single-use applications. In one particularembodiment, flexible bag 12, the pump 14,

It should be appreciated that while the embodiments of the pump 14described herein are described in the context of a diaphragm pump, theinvention is not limited to diaphragm pumps. Other pumps may also beused. These include by way of illustration, centrifugal pumps, or otherpositive displacement pumps. For example, if mammalian cells are notused in the flexible bag 12, the gentle pumping action of the diaphragmpump may not be needed in which case other pumps such as a centrifugalpump may be used. Such pumps would be integrated into or connected tothe flexible bag 12 or the tank 82 using a similar pump head asdescribed herein, albeit one operates using a different pumpingmechanism. In addition, while the embodiments of the vessels 10 with anintegrated pump 14 have been described as using a conventional rotarymotor to power the pump 14, in other embodiments a different type ofpump driver can be employed to pump fluid from the vessel 10. Forexample, for a diaphragm pump 14, the diaphragms 44 may be actuated inthe desired sequence and speed using servos associated with eachdiaphragm 44 to generate the same pumping action.

While embodiments of the present invention have been shown anddescribed, various modifications may be made without departing from thescope of the present invention. Moreover, it should be appreciated thataspects of one embodiment may be utilized in other embodiments describedherein. Thus, feature of one embodiment may be substituted or used inother embodiments. This includes, by way example, the mixing adaptors,ports, pumps, pump connection types, motors, and the like. In addition,while the embodiments described herein have largely been described beingused in the context of a bioprocess or pharmaceutical operation, theembodiments are not limited to those applications. For example, theconcepts and embodiments described herein may be applied to high puritychemical systems or in other industries. The invention, therefore,should not be limited except to the following claims and theirequivalents.

What is claimed is:
 1. A bioprocess vessel having an integrated pumpcomprising: a flexible bag defining an interior volume and having abottom surface, the bottom surface containing an aperture therein forthe passage of fluid; a pump head and having an inlet and an outlet, thepump head secured to the bottom surface of the flexible bag with aplurality of fasteners and further including a plurality of diaphragms,each diaphragm associated with a check-valve, wherein sequentialactuation of the plurality of diaphragms pumps fluid from the interiorvolume of the flexible bag into the inlet and out of the outlet.
 2. Thebioprocess vessel of claim 1, further comprising a mixing adaptersecured to the pump head and disposed at least partially in the interiorvolume of the flexible bag, the mixing adapter at least partiallycovering the inlet of the pump head.
 3. The bioprocess vessel of claim1, the pump head further comprising a nutating disk or wobble plateconfigured to sequentially actuate the plurality of diaphragms.
 4. Thebioprocess vessel of claim 3, further comprising a detachable motorsecured to the pump head.
 5. The bioprocess vessel of claim 1, furthercomprising a plurality of actuators configured to sequentially actuatethe plurality of diaphragms.
 6. The bioprocess vessel of claim 1,further comprising a gasket interposed between the pump head and bottomsurface of the flexible bag.
 7. A bioprocess vessel having an integratedpump comprising: a substantially rigid container formed from a resin orpolymer material defining an interior volume and having a bottomsurface; and a pump head and having an inlet and an outlet, the pumphead secured to the bottom surface of the substantially rigid containerwith a plurality of fasteners and further including a plurality ofdiaphragms, each diaphragm associated with a check-valve, whereinsequential actuation of the plurality of diaphragms pumps fluid from theinterior volume of the substantially rigid container into the inlet andout of the outlet.
 8. The bioprocess vessel of claim 7, furthercomprising a mixing adapter secured to the pump head and disposed atleast partially in the interior volume of the substantially rigidcontainer, the mixing adapter at least partially covering the inlet ofthe pump head.
 9. The bioprocess vessel of claim 7, the pump headfurther comprising a nutating disk or wobble plate configured tosequentially actuate the plurality of diaphragms.
 10. The bioprocessvessel having an integrated pump of claim 9, further comprising adetachable motor secured to the pump head.
 11. The bioprocess vessel ofclaim 7, further comprising a plurality of actuators configured tosequentially actuate the plurality of diaphragms.
 12. The bioprocessvessel of claim 7, further comprising a lid having one or more portsformed therein.
 13. The bioprocess vessel of claim 12, furthercomprising a rotating shaft extending through the lid and into theinterior of the substantially rigid container and having an impellerthereon.
 14. The bioprocess vessel of claim 7, further comprising agasket interposed between the pump head and bottom surface of theflexible bag.